The serotonin syndrome is a potentially life-threatening adverse drug experience that results from therapeutic drug use, intentional self-poisoning or inadvertent interactions between drugs. The manifestations of the serotonin syndrome range from mild to fatal. (Boyer and Shannon, NEJM, 2005; Jones and Story, Anaesth Intensive Care, 2005; Sporer, Drug Safety, 1995). The serotonin syndrome is not to be confused with iatrogenic serotonergic side effects that usually manifest with the use of serotonin agonists or serotonergic drugs
This syndrome is characterized by a constellation of symptoms. Patients with mild cases may be afebrile but have tachycardia, shivering, diaphoresis, or mydriasis. The neurologic examination may reveal intermittent tremor or myoclonus, as well as hyperreflexia. In moderate cases of the serotonin syndrome, patients may have tachycardia, hypertension, and hyperthermia. A core temperature of up to 40° C. is common in moderate intoxication. Common features include mydriasis, hyperreflexia, clonus, hyperactive bowel sounds, diaphoresis, mild agitation or hypervigilance, as well as pressured speech. Patients with severe cases of the serotonin syndrome may have severe hypertension and tachycardia that may progress to frank shock. Such patients may have delirium, muscular rigidity and hypertonicity. Although no laboratory tests confirm the diagnosis of the serotonin syndrome, lab abnormalities that occur in severe cases include metabolic acidosis, rhabdomyolysis, elevated levels of AST, ALT and creatinine, seizures, renal failure, and disseminated intravascular coagulopathy (DIC). (Boyer and Shannon, NEJM, 2005; Jones and Story, Anaesth Intensive Care, 2005; Sporer, Drug Safety, 1995).
The incidence of the serotonin syndrome appears to have increased with the widespread use of drugs that enhance the effects of serotonin, through serotonin reuptake inhibition, direct agonism at serotonin receptors or through unknown mechanisms, or through effects at receptors other than serotonin (proserotonergic agents). A wide variety of proserotonergic drugs, taken alone or in combination have been implicated in the causation of the serotonin syndrome (Boyer and Shannon, NEJM, 2005; Jones and Story, Anaesth Intensive Care, 2005; Sporer, Drug Safety, 1995). These include the now ubiquitous selective serotonin-reuptake inhibitors (SSRIs), e.g., citalopram, fluoxetine, fluvoxamine, paroxetine and sertaline; selective serotonin-norepinephrine reuptake inhibitors (SNRIs), e.g, venlafaxine, milnacipran; tricyclic and non-tricyclic antidepressants, e.g., buspirone, clomipramine, nefazodone, trazadone; monoamine oxidase (MAO) inhibitors, e.g., clorgiline, isocarboxazid, moclobemide, phenelzine and selegiline; antiepileptics, e.g., valproate; analgesics, e.g., fentanyl, meperidine, pentazocine and tramadol; antiemetic agents, e.g., granisetron, metoclopramide and ondansetron; antimigraine drugs, e.g., sumatriptan; bariatric medications, e.g., sibutramine; antibiotics, e.g., linezolide (a MAOI) and ritonavir (via CYP-450 3A4 inhibition); antitussives, e.g. dextromethorphan; dietary supplements and herbal products, e.g., tryptophan, Hypericum perforatum (St. John's wort), Panax ginseng (ginseng); and lithium. (Boyer and Shannon, NEJM, 2005; Jones and Story, Anaesth Intensive Care, 2005; Sporer, Drug Safety, 1995).
According to the Toxic Exposure Surveillance System (TESS), in 2002, there were 26,733 reported cases of exposure to selective serotonin-reuptake inhibitors (SSRIs) that caused serious toxic effects in 7,349 individuals and resulted in 93 fatalities (Isbister et al, J Toxicol Clin Toxicol 2004; Watson et al, Am J Emerg Med 2003).
The prevalence of the serotonin syndrome has relied on post-marketing surveillance reports, one of which identified an incidence of 0.4 per 1000 patient-months for patients who were taking the antidepressant nefazodone (Mackay et al, Br J Gen Pract 1999). The precise prevalence of the serotonin syndrome is difficult to assess; it is reported that approximately 85 percent of clinicians are unaware of the serotonin syndrome as a clinical diagnosis ((Mackay et al, Br J Gen Pract 1999). The serotonin syndrome occurs in approximately 14 to 16 percent of individuals who overdose on SSRIs (Isbister et al, J Toxicol Clin Toxicol 2004).
Clarkson et al (J Forensic Sci, 2004) reviewed a series of 66 deaths in Washington State between 1995-2000 in which tramadol was detected in the decedent's blood, in order to assess the role tramadol was determined to have played. Tramadol is an analgesic that exerts its effects through inhibition of reuptake of serotonin and norepinephrine, and through opioid agonism. Tramadol was consistently found together with other analgesic, muscle relaxant, and CNS depressant drugs. The investigators found that death was rarely attributable to tramadol alone. However, tramadol was a significant contributor to lethal intoxication when taken in excess with other drugs, via the potential interaction with serotonergic antidepressant medications (e.g., amitriptyline, nortriptyline, trazadone).
Serotonin syndrome can occur with the (i) initiation of therapy with a proserotonergic agent; (ii) the addition of a second proserotonergic agents; and (iii) intentional or accidental overdose with one or several proserotonergic agents. Proserotonergic agents are frequently used in patients with primary psychopathology (major depression, schizophrenia), in individuals who have chronic pain and those with chronic pain and comorbid depression or other affective disorders. Such populations are particularly predisposed to concomitant therapy with multiple proserotonergic drugs, other polypharmacy, drug and alcohol abuse and suicidal ideation. Consequently, patients receiving proserotonergic agents are at particular risk for accidental or intentional overdose with one or several prescribed or street drugs implicated in the serotonin syndrome.
Proserotonergic agents are also frequently used as primary therapy or in combination with conventional analgesics for the treatment of painful peripheral neuropathic pain (e.g., painful diabetic neuropathy, postherpetic neuralgia, etc) and central neuropathic pain (e.g, spinal cord injury pain, post-stroke pain, etc).
Over the past decade, there has been a growing appreciation of the value of extended release (also know as sustained release, controlled release and modified release) formulations in improving patient convenience and compliance for chronic conditions such as depression or chronic pain. Conventional (so called “immediate-release” or “short acting”) medications provide short-lived plasma levels, thereby requiring frequent dosing during the day (e.g., 4, 6 or 8 hours) to maintain therapeutic plasma levels of drug. In contrast, extended release formulations are designed to maintain effective plasma levels throughout a 12 or 24-hour dosing interval. Extended release formulations result in fewer interruptions in sleep, reduced dependence on caregivers, improved compliance, enhanced quality of life outcomes, and increased control over the management of their disease. In addition, such formulations can provide more constant plasma concentrations and clinical effects, less frequent peak to trough fluctuations and fewer side effects, compared with short acting drugs (Sloan and Babul, Expert Opinion on Drug Delivery 2006; Babul et al. Journal of Pain and Symptom Management 2004; 28:59-71; Matsumoto et al., Pain Medicine 2005; 6:357-66; Dhaliwal et al., Journal of Pain Symptom Management 1995; 10:612-23; Hays et al., Cancer 1994; 74:1808-16; Arkinstall et al., Pain 1995; 64:169-78; Hagen et al., Journal of Clinical Pharmacology 1995; 35:38-45; Peloso et al., Journal of Rheumatology 2000; 27:764-71).
However, such medications are not without drawbacks. Commercially available immediate-release formulations are designed to release a small amount of drug into the systemic circulation over several hours. New, extended release formulations are designed to gradually release their much larger drug load over a 12 or 24-hour period. Experience with extended release formulations of the pain reliever, oxycodone (OxyContin®) has shown that intentional crushing, tampering or extraction of the active ingredient from the formulation by addicts and recreational drug users destroys the controlled-release mechanism and results in a rapid surge of drug into the bloodstream, with the entire 12 or 24-hour drug supply released immediately with potential for toxic effects.
In the case of proserotonergic drugs, accidental or intentional crushing or extraction or overdose will result in a surge of high blood levels (serotonin excess). Studies have demonstrated that serotonin excess, leading to the serotonin syndrome, may be a result of a single proserotonergic drug or more frequently, from the combined effect of multiple proserotonergic drugs (e.g., the analgesic tramadol with an SSRI). If not properly diagnosed and treated, serotonin syndrome can lead to life-threatening complications and death.
The onset of symptoms of the serotonin syndrome is usually rapid, with clinical manifestations frequently occurring within minutes after a change in medication or self-poisoning (Mason et al, Medicine, 2000). More than half the patients with the serotonin syndrome present within six hours after initial use, misuse or abuse of medication, an overdose, or a change in dosing. (Mason et al, Medicine, 2000). Patients with mild symptoms may present with subacute or chronic symptoms, while those with severe intoxication may progress rapidly to death. It is believed that the serotonin syndrome does not resolve spontaneously as long as precipitating agents continue to be administered.
Management of the serotonin syndrome involves the removal of the precipitating drugs, supportive care, control of agitation, administration of 5-HT2A antagonists and control of autonomic instability and any hyperthermia. Many cases of the serotonin syndrome typically resolve within 24 hours after the initiation of therapy and the discontinuation of serotonergic drugs, but symptoms may persist in patients taking drugs with long elimination half-lives, active metabolites, or a protracted duration of action. (Boyer and Shannon, NEJM, 2005; Jones and Story, Anaesth Intensive Care, 2005; Sporer, Drug Safety, 1995).
According to a recent state of the art review Boyer and Shannon, NEJM, March 2005), the serotonin syndrome can be avoided by “a combination of pharmacogenomic research, the education of physicians, modifications in prescribing practices, and the use of technological advances. The application of pharmacogenomic principles can potentially protect patients at risk for the syndrome before the administration of serotonergic agents. Once toxicity occurs, consultation with a medical toxicologist, a clinical pharmacology service, or a poison-control center can identify proserotonergic agents and drug interactions, assist clinicians in anticipating adverse effects, and provide valuable clinical decision-making experience. The avoidance of multidrug regimens is critical to the prevention of the serotonin syndrome. If multiple agents are required, however, computer-based ordering systems and the use of personal digital assistants can detect drug interactions and decrease reliance on memory in drug ordering. Post-marketing surveillance linked to physician education has been proposed to improve awareness of the serotonin syndrome.”
There is no prior art on pharmaceutical formulations of prosertonergic agents that have a reduced risk of producing the serotonin syndrome.
There is no prior art on pharmaceutical formulations of opioid agonist prosertonergic agents that have a reduced risk of producing the serotonin syndrome.